Method and system for improving stimulation of excitable tissue

ABSTRACT

A method for optimization of the stimulation pattern of a set of implanted electrodes in excitable tissue of a patient is disclosed, wherein it comprises the steps of: (a) choosing a first group of a certain number of from said set of implanted electrodes, (b) stimulating the excitable tissue electrically by said first group of electrodes, (c) registering information provided by the patient, (d) assigning each electrode of said first group of electrodes a value related to said information, wherein these steps are repeated for one or more further groups of said certain number of electrodes chosen from said set of implanted electrodes, wherein each electrode may be included in one or several groups, wherein the total assigned value for each electrode is calculated, and wherein electrodes having a total assigned value exceeding a predetermined value or a predetermined number of the electrodes having the highest total assigned value are chosen to be included in said stimulation pattern, as well as a method for treatment or alleviation of a disease or condition by use of a set of electrodes whose stimulation pattern has been optimized with said method, and a system for optimization of the stimulation pattern.

This application claims priority under 35 USC 119(a)-(d) to SE patentapplication No. 1551013-4 filed Jul. 10, 2015, and PCT patentapplication No. PCT/SE2016/050534 filed Jun. 3, 2016, the entirecontents of both of which are incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention refers to a method for optimization of thestimulation pattern of implanted electrodes in excitable tissue of apatient and to a system for performing said optimization.

BACKGROUND ART

Deep Brain Stimulation (DBS) was introduced for the treatment ofneurological diseases such as Parkinson's disease in the eighties. Thetechnique stimulates nervous tissue using an electrode device(alternatively called probe) that is implanted into deep nuclei of thebrain. The mechanisms underlying the therapeutic effects are only partlyunderstood but are thought to involve inhibition of abnormal neuralactivity. The DBS probe design used in the clinic has remained largelyunchanged although more channels have been added to present versions.However, these probes still exhibit substantial limitations instimulation specificity and biocompatibility. Consequently, such probesare prone to produce side effects and loss of therapeutic efficiencyover time. At least three features of the design underlie theseshortcomings: 1) detailed control of the distribution of current in thetarget tissue is prevented by the large size of the active electrodesurfaces of the DBS electrodes combined with a distribution of theseelectrodes along the same probe, 2) it is difficult to predict theoptimal stimulation sites in a given patient as the neural mechanismsunderlying the beneficial effects of DBS are not fully understood andare due to individual variation in functional anatomy, 3) currentelectrode designs produce substantial glial scarring, that displacesneurons away from the active electrode sites. In turn, the glialscarring necessitates higher current intensities to achieve neuralstimulation and results in a larger stimulation spread. A furtherproblem is the shortening of battery life due to high currentintensities resulting in repeated recharging or surgical replacement ofthe battery.

The state of art of devices for implantation into soft tissue alsocomprises microelectrodes. Microelectrodes have a wide field ofapplication in medicine and related fields. In principle, electricsignals emanating from single nerve cells or group of cells can berecorded. Single nerve cells or group of cells can also be electricallystimulated by such devices, and their reaction to such stimulation canbe monitored. Several types of multichannel microelectrodes are known inthe art (see e.g. WO 2007/040442, WO 2008/091197, WO 2009/075625, WO2010/144016, WO 2012/025596 and WO 2013/191612).

US 2006/0195159 discloses a method of selecting a subset of electrodesin a stimulator device implanted in a patient in order to obtain anoptimal therapeutic patient outcome.

US 2012/0302912 discloses a method for stimulation treatment whereinelectrical stimulation is given via an electrode array in accordancewith a set of stimulation parameters relating to both electrodecombinations and electrical pulse parameters.

Multichannel electrodes offer the possibility of providing a precisestimulation pattern. Given that the functional anatomy of the brain isnot identical for different patients due to e.g. congenital variations,structural changes caused by aging and degenerative diseases, and toexperience dependent alterations in neuronal networks, the precisestimulation pattern causing a beneficial effect with minimal sideeffects needs to be evaluated in each patient. It is known to relate theimplanted electrodes to known anatomical landmarks using imagingtechniques such as computer tomography (CT) and magnetic resonanceimaging (MRI) and observing the effects in the patient caused by thestimulation through the implanted electrodes. However, in many instancesbeneficial effects and side effects of a given stimulation pattern maytake considerable time to establish. Hence, the time consumption tooptimize the stimulation pattern becomes problematic when usingmultichannel electrode devices comprising a large number of electrodes.

Furthermore, it is also desirable to define a therapeutically usefulstimulation pattern while keeping the energy consumption of thestimulation as low as possible, since this will reduce the risk ofstimulation produced injury to the tissue and enhance the battery lifetime of the stimulating device connected to the implanted electrodes.

The objects of the present invention are to solve at least some of theseproblems and thereby improve the stimulation of excitable tissue, suchas neuronal tissue or endocrine tissue of a patient with a view tocuring or alleviating different diseases and disorders, including bothphysiological and psychological conditions. Additional objects willbecome obvious from the detailed description of the invention.

SUMMARY OF THE INVENTION

An object with the present invention is to eliminate at least some ofthe above-mentioned problems and to provide a method and a system foroptimization of the stimulation pattern of a set of implanted electrodesin excitable tissue of a patient, the patient being an animal or ahuman.

According to the invention, this object is achieved by means of a methodand a system of the type mentioned by way of introduction, which havethe features presented in the independent method claim and system claim,respectively. Different embodiments of said method and system arepresented in the dependent claims, respectively.

More precisely, in a first aspect the present invention refers to amethod for optimization of the stimulation pattern of a set of implantedelectrodes in excitable tissue of a patient, wherein it comprises thesteps of choosing a first group of a certain number of electrodes fromsaid set of implanted electrodes, stimulating the excitable tissueelectrically by said first group of electrodes, registering informationprovided by the patient, assigning each electrode of said first group ofelectrodes a value related to said information, and wherein the methodis repeated for one or more further groups of said certain number ofelectrodes chosen from said set of implanted electrodes, wherein eachelectrode may be included in one or several groups, wherein the totalassigned value for each electrode is calculated, and wherein electrodeshaving a total assigned value exceeding a predetermined value are chosento be included in said stimulation pattern.

In a second aspect the present invention refers to the method accordingto said first aspect, wherein it also comprises steps for the reductionof the energy consumption.

In a third aspect the present invention refers to a method for treatmentor alleviation of a disease or condition by use of a set of electrodeswhose stimulation pattern has been optimized with the method accordingto claim 1, wherein the disease or condition is chosen from the groupconsisting of brain and/or spinal damage, lost functions, pain,Parkinson's disease, tremor, motor disorders, choreatic and otherinvoluntary movements, memory disorders, Alzheimer's disease,degenerative diseases, epilepsy, mood disorders, aggression, anxiety,phobia, affect, sexual over-activity, impotence, eating disorders, sleepdisorders, such as narcolepsy, attention disorders, stroke, damage ofthe brain, damage of the spinal cord, bladder disorders after spinalcord injury, bowel disorders after spinal cord injury, spasticity,somatosensory disorders, auditory disorders, visual disorders, andolfactory disorders.

In a fourth aspect the present invention refers to a system foroptimization of the stimulation pattern of a set of implanted electrodesin excitable tissue of a patient and for treatment or alleviation of adisease or disorder with the method according to the present inventionis also provided. The system comprises a set of electrodes having theability to be implanted in excitable tissue of a patient, a stimulationdevice connected to said set of electrodes and having the ability tostimulate said excitable tissue via said set of electrodes, a firstcomputer program connected to the stimulation device and having theability to transform information provided by the patient to an assignedvalue for a tested group of electrodes, to calculate a total assignedvalue for each electrode, and to choose a preferred set of electrodes tobe used for stimulation treatment.

In a fifth aspect the present invention refers to a method foroptimization of the stimulation specificity and the energy consumptionof implanted electrodes in excitable tissue of a patient, wherein itcomprises the step of electrical stimulation of excitable tissue betweenone or more combinations of electrode pairs in a cluster of electrodes,optionally comprising the electrodes chosen to be included in astimulation pattern according to the first aspect, or electricalstimulation between one or more combinations of electrode pairs in twoor more clusters of electrodes, wherein the two electrodes of saidelectrode pairs do not belong to the same cluster, wherein said two ormore clusters of electrodes optionally comprises the electrodes chosento be included in a stimulation pattern according to the first aspect,wherein the electrical stimulation between different combinations ofelectrode pairs in a cluster of electrodes, or the electricalstimulation between different combinations of electrode pairs in two ormore clusters of electrodes, creates a directed electrical field;wherein the effect of the directed electrical field is assessed aftereach stimulation step by registering information provided from thepatient in view of a therapeutic effect and by monitoring the energyconsumption, followed by choosing the electrode pair or pairs which giverise to the lowest energy consumption while still giving a therapeuticeffect, or assigning each electrode pair a value related to saidinformation provided by the patient and the energy consumption; andchoosing the electrode pair or pairs which give(s) rise to the mostfavorable assigned value.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically shows a system according to the present inventioncomprising a first computer program P1 and a stimulation device S whichis capable of stimulating electrodes 3 implanted in excitable tissue 2of a human or an animal.

FIG. 2 schematically shows the system in FIG. 1, further comprising aregistration device R, a second computer program P2, and a database DB.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS THEREOF

First, some specific expressions and terms used throughout theapplication text will be defined.

The expression “optimization of the stimulation pattern of a set ofimplanted electrodes” is to be understood as finding a satisfactorystimulation pattern. The found stimulation pattern need not be the besttheoretical pattern, but rather a “good enough” pattern. The word“optimal” is to be understood in accordance with the above.

Endocrine tissue or endocrine organs are tissues or organs which secretehormones into the circulation.

A “nucleus” (plural nuclei) is an anatomically defined cluster ofneurones, e.g. the subthalamic nucleus, nucleus habenula etc. Thewording nucleus should not limit the use.

“Anatomical compartment” is defined as a structure that is delineatedanatomically, for example the thalamus, cortex cerebri, the subthalamicnuclei, and the dorsal horn of the spinal cord.

A “subnucleus” is defined as a subcompartment of a nucleus, such as theventroposterior nucleus or ventromedial nucleus of thalamus or part ofthe ventroposterior nucleus involved in face somatosensory functions.

An “activity pattern” is defined as a discharge pattern of neurons. Theactivity pattern may be measured as action potentials and/or local fieldpotentials.

“Search field” is defined as a predetermined subgroup of electrodes orsubgroup of stimulation parameters for a given group of electrodes. Insome embodiments, “search field” may be defined as including allelectrodes.

All electrodes are stimulated against a reference electrode, unlessotherwise stated. The reference electrode may be placed outside thestimulated area, unless otherwise stated. The reference electrode shouldhave a low impedance to reduce energy consumption during stimulation.

“Electrode” is defined as an implanted lead including the non-insulatedpart where current from the stimulator can be passed into the tissue.

According to the above defined first aspect of the invention, the aboveand other objects of the invention are achieved, in full or at least inpart, by the method as defined in the independent method claim.

When implanting a larger number of electrodes into excitable tissue,e.g. neuronal tissue, it is most likely that some of the implantedelectrodes give rise to no effect or to negative effects when used forstimulation of the neuronal tissue. It is also most likely thatstimulation of a combination of electrodes will give the best effect,i.e. decreased or abolished symptoms with as few negative effects aspossible. The method according to the present invention may be used tofind such an optimal combination of electrodes. In addition, the methodaccording to the present invention may also be used to find optimalstimulation parameters for each electrode in the combination.

The present invention provides a method for finding the optimal set ofelectrodes for stimulation as well as a method to reduce the number ofelectrodes needed to obtain a satisfactory result.

The stimulation of the targeted tissue does preferably not start untilthe patient actively instructs the system to do so. Thus, the patient isgiven full control over the situation.

The time period under which stimulation occurs may be set in advance.

The time period between different stimulations may be set in advance.

Each electrode may be included in one or several tested groups.

The number of electrodes included in each group is dependent on thetotal number of implanted electrodes. Preferably, 3-15 electrodes areincluded in each group. Typically, 20% of the total number implantedelectrodes are used in each group which is used for stimulation. Everysingle electrode may be tested at least 3 times, preferably at least 5times, more preferably at least 10 times, most preferably at least 12-15times. Every single electrode may be tested even more times.

Generally, the stimulation is carried out at 0.1-5 V, preferably below 2V and occasionally as high as at 10 V.

Each test stimulation comprises a train of electrical pulses. Each pulsein the train may be longer than 2 ms. The internal frequency ofstimulation pulses may exceed 50 Hz. Each test stimulation may have aduration of at least 100 ms, preferably at least 1 s, or most preferablyat least 5 s.

Each pulse is preferably balanced with respect to the charge emittedfrom the electrode. For example, a symmetric biphasic square wave whichinitially has a negative potential followed by a positive potential.Other wave shapes are within the scope of the invention.

The total assigned value for each electrode may be calculated as the sumof all values assigned to the electrode. Median values are preferredwhen the sample size is small, such as for samples less than 7 tests.

Alternatively, the total assigned value for each electrode may becalculated as the average value of all values assigned to the electrode.

The total assigned value for each electrode may be calculated as themedian value of all values assigned to the electrode.

The predetermined value involved in the method according to the presentinvention is determined depending on the scale used. E.g., a symmetricscale covering the span from −100 to +100 may be used, wherein −100indicates maximal adverse effects and +100 indicates total relief ofsymptoms. The threshold may then be >0, i.e. when the electrode addspositively to the therapy. Alternatively, the threshold may be setto >30 by the reason that the placebo effect normally appears in thatregion and that a symptom release of at least 30% is desirable if thetreatment is to be competitive. In certain applications, the thresholdmay be set to >50. Said value obtained for each group of electrodes isassigned on a digital or analog scale, wherein values on one side of themidpoint correspond to therapeutic effect and values on the other sideof the midpoint correspond to adverse effects. In other applications,e.g. when a visual analog scale is used, 0 is to the right and 100 tothe left. Usually 0 means no pain and 100 is maximal pain. Thus, in thiscase the best values are to the right.

The total assigned value for each electrode may be calculated as the sumof all values assigned to the electrode. This requires that eachelectrode has been stimulated the same number of times.

Alternatively, the total assigned value for each electrode may becalculated as the average value of all values assigned to the electrode.

The total assigned value for each electrode may be calculated as themedian value of all values assigned to the electrode. The total assignedvalue for each electrode may in one embodiment be the sum of a componentdescribing the effect of the stimulation on the symptoms which are to betreated and of a component describing any side effects of thestimulations.

The total assigned value for each electrode may be comprised of acomponent describing the effect of the stimulation on the symptoms whichare to be treated and a YES or NO regarding the side effects of thestimulations.

Combinations of the above-mentioned ways to calculate the total assignedvalue may be utilized in one embodiment.

If one specific electrode is associated with a negative effect in all orin a majority of the tests, such as a low degree of effect on thecondition or disease which is treated, or such as a side effect, thegroups may be tested again without this specific electrode.

One advantage of the current invention is that, through this method,electrodes which give rise to the desired therapeutic effect may befound in a time efficient manner. In addition, electrodes thestimulation of which give rise to undesired effects may be identified ina time efficient manner and may thus be excluded from the used set ofelectrodes.

The time needed to find electrodes which give rise to the desiredtherapeutic effect depends on how often the test pulses may be given andthe time needed to evaluate each test. For example, if the effect of thestimulation is immediate, each test cycle may take about 30 s. The testcycle includes the feedback provided by the patient. Thus, if the effectof the stimulation has a long onset time, the evaluation of each testcycle is prolonged.

The interval between test cycles is influenced for example by theduration of the effect, i.e. the time for return of the symptoms. ForDBS in treatment of Parkinson's disease both onset latency and durationis relatively short, typically less than one minute.

For example, if the effect of 30 electrodes is to be evaluated, and 20%of the electrodes are tested in each test cycle, and each electrode isto be tested 10 times, a total number of 50 test cycles must beperformed. If each test cycle takes 1 min, the electrodes which giverise to the desired therapeutic effect may be found in 50 min. If eachof the 30 electrodes were to be tested individually, it would take 300min to find the electrodes which give rise to the desired therapeuticeffect.

Another advantage is that combinations of electrodes which give rise tothe desired therapeutic effect may be found.

The method according to the present invention may be used foroptimization of the stimulation pattern of a set of implanted electrodesin order to treat and/or alleviate Parkinson's disease.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate pain. Thepain may be chronic pain. The pain may be neuropathic pain.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate emotionaldisorders, e.g. depression and anxiety.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviateepilepsia.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviateconditions involving delusions.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviatepsychological disorders, e.g. Tourette's syndrome and obsessivecompulsive disorder (OCD).

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate eatingdisorders, e.g. anorexia nervosa and bulimia.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate obesity.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate cognitivedisorders, e.g. Alzheimer's disease.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate sleepdisorders, e.g. narcolepsy.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to treat and/or alleviate highblood pressure.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to regulate the body temperature.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to regulate circadian rhythms.

The method may be used for optimization of the stimulation pattern of aset of implanted electrodes in order to regulate the biological clock ofa patient.

The patient may be a human or an animal, and e.g. chronic pain oraggression in pets may be treated.

According to one embodiment of the present invention, the method may bepreceded by a step of stimulating all electrodes at the same time whileincreasing the stimulation strength. Threshold(s) for adequatetherapeutic effects and significant adverse effects can thus beestablished and used in the search routine above, more precisely for usein the step of stimulating the excitable tissue.

Stimulation strength may be amplitude in voltage or in current.

For example, the thresholds for adequate therapeutic effects can then beused when searching for effective subgroups as above. One advantage ofthis embodiment is that the patient is gradually acquainted to theeffect of stimulation. Another advantage is that a stimulation strengthis established, which is used in the following steps. This minimizes therisk of stimulating with a too high strength which could lead to seriousnegative effects.

Energy saving is one aim since this prolongs the battery endurance butdoes not necessarily result in impaired therapy. Reducing the group ofimplanted electrodes to a sub-group of electrodes which are used forstimulation still providing satisfactory results will significantlyreduce the energy expenditure.

The invention is based on the insight that reducing the energyconsumption by using a sub-selection of electrodes which produceacceptable results will also often increase the specificity of thestimulation and reduce the incidence of side effects by avoidingstimulation of electrodes or stimulation intensities that produceundesired results.

Thus, as disclosed above, a second aspect of the present inventionrefers to a method for optimization of the stimulation pattern which iscarried out as two separate optimizations. The first optimizationcomprises the steps of choosing a first group of a certain number ofelectrodes from said set of implanted electrodes, stimulating theexcitable tissue electrically by said first group of electrodes,registering information provided by the patient, assigning eachelectrode of said first group of electrodes a value related to saidinformation, and wherein the method is repeated for one or more furthergroups of said certain number of electrodes chosen from said set ofimplanted electrodes, wherein each electrode may be included in one orseveral groups, wherein the total assigned value for each electrode iscalculated, and wherein electrodes having a total assigned valueexceeding a predetermined value are chosen for a group of electrodes tobe included in said stimulation pattern. The subsequent secondoptimization is an optimization of stimulation parameters for theelectrodes chosen to be included in said stimulation pattern accordingto claim 1 in view of the energy consumption needed for said chosenelectrodes to give rise to a therapeutic effect, wherein the secondoptimization comprises the steps of varying one or more of thestimulation parameters for said chosen electrodes in a stimulation testseries; registering information provided by the patient; monitoring theenergy consumption for each stimulation test where the stimulation givesrise to a therapeutic effect; and choosing, as the stimulationparameters, the parameters which give rise to the lowest energyconsumption while still giving a therapeutic effect; or assigning eachstimulation test a value related to said information provided by thepatient and the energy consumption; and choosing the parameters whichgive rise to the most favorable assigned value.

The parameters which may be varied comprise the pulse width, theamplitude of the stimulation pulse, the stimulation strength, thestimulation frequency, the shape of the stimulation pulse, the polarity,the stimulation type as to the degree of randomization and the temporalpattern of stimulation, e.g. periods of higher frequency followed bylower frequencies or quiescence as when burst stimulation is used,wherein the internal frequency of pulses in the burst is higher than thefrequency of the bursts. One example is to use bursts with 3-10 pulsesat an internal frequency exceeding 200 Hz, wherein the bursts areseparated by a period of less frequent stimulation. Another pattern isto use amplitude modulation or frequency modulation. In the first caseamplitude modulation means that the pulse amplitude is varied over acertain time cycle between defined values. Frequency modulation meansthat the frequency is varied in same way. The modulation may be e.g.sinusoidal variation of pulse amplitude or frequency.

Alternatively, a first group of electrodes in the first optimizationstep is assigned a value based on the information provided by thepatient and the energy consumption needed to give rise to a therapeuticeffect.

Each group of electrodes may be tested several times, but with differentstimulation parameters. The parameters which may be varied comprise thepulse width, the amplitude of the stimulation pulse, the stimulationstrength, the stimulation frequency, the temporal pattern ofstimulation, the shape of the stimulation pulse, the polarity, and thestimulation type as to the degree of randomization.

The assigned value may be a function of the therapeutic effect inducedby stimulation by the electrode group and of the energy consumptionneeded. In this way, the energy consumption may be optimized at the sametime as a therapeutic effect is ensured.

Alternatively, the assigned value will be a weighted function. Forexample, the therapeutic effect and the energy consumption are given thesame weight. Another example is that the weight of the energyconsumption is dependent on the effect which is reached and grows inimportance above a therapeutic threshold (good enough).

In the case when the assigned value is based on the information providedby the patient and the energy consumption needed to give rise to atherapeutic effect, the function may include threshold values for theeffect and/or the energy consumption such that a value is assigned onlywhen the therapeutic effect is above a certain predetermined value andwhen the energy consumption is below a certain predetermined value.

Alternatively, the first optimization step is preceded by a step ofinitially stimulating all electrodes while stepwise increasing thestimulation strength. As stated above, one advantage of this embodimentis that the patient is gradually acquainted to the effect ofstimulation. Another advantage is that a stimulation strength isestablished, which is used in the following steps. This minimizes therisk of stimulating with a too high strength which could lead to seriousnegative effects, such as pain, panic, vertigo, speech problems, andemotional disturbances such as aggression. The patient assigns atherapeutic value to each step and notes the occurrence of adverseeffects. In this way an overall view is initially created. It may bethat no adverse effect is encountered. If so, the method above may beused to fine tune the energy consumption.

According to one embodiment of the invention, the set of implantedelectrodes comprises a plurality of microelectrodes. In this context, amicroelectrode is defined as electrodes having a diameter of less than100 μm, i.e. the lead has a diameter of less than 100 μm. However,active sites in the electrode may have a diameter larger than 100 μm.The length of the electrode may be of any length suitable for thetarget. The part of the electrode used to emit current to the tissue(usually the non-insulated part of the electrode) is not limited insize.

According to another embodiment of the invention, the electrodes may belarger, such as e.g. electrodes used for spinal cord stimulation.

Compared to conventional electrodes used for e.g. DBS (typically about 1mm) in diameter, an individual electrode in a microelectrode is verysmall and can thus be very specific regarding the neuronal tissue whichit stimulates. This depends on how large the active surface is. In somecases, such an electrode can be regarded as stimulating only the mostadjacent cells. This gives the possibility to tailor the stimulationpattern and parameters to the individual patient and to decrease thenegative effects that stimulation of some cells or groups of nearbycells give rise to. Such negative effects may be hallucinations,discomfort such as nausea, anxiety, aggression, or other emotionaldisturbances.

One advantage of microelectrodes is that such small electrodes, due totheir smaller size, may be integrated into nerve cell circuits betterthan a larger electrode. This is especially important since e.g.specific stimulation within sub-compartments in a tissue volume of lessthan approximately 1 mm³ requires microelectrodes that are much smallerthan conventional electrodes for DBS, which are in the mm scale.

Another advantage is that microelectrodes, due to their smaller size,usually are much more biocompatible than larger electrodes (Thelin J,Jörntell H, Psouni E, Garwics M, Schouenborg J, Danielsen N, LinsmeierCE. Implant size and fixation mode strongly influence tissue reactionsin the CNS. PLoS One. 2011 Jan. 26; 6(1)e16267). Thus, such electrodesgive rise to less glial scarring, reducing the problem of having toincrease the current intensities to achieve neural stimulation. Theproblem with glial scarring is that it increases the distance from theelectrodes to viable neurons.

According to a further embodiment, the set of implanted electrodescomprises electrodes which have active sites for charge ejection locatedon different physical entities. Examples of such electrodes areelectrode arrays or electrode bundles in which several individualelectrodes together make up the probe (Lind G, Linsmeier CE, Thelin J,Schouenborg J, Gelatine-embedded electrodes—a novel biocompatiblevehicle allowing implantation of highly flexible microelectrodes. JNeural Eng. 201 August; 7(4):046005. Epub 201 June 16). In other words,the electrodes or active sites are physically separated in targettissue. In this context, “active site for charge ejection” is thelocation on an electrode from where most of the stimulation istransferred to the surrounding tissue.

An advantage of such electrodes is that they, since they are located ondifferent physical entities, can be spread throughout the tissue whichis to be stimulated or spread on the border of the tissue which is to bestimulated and thus can limit the stimulated volume necessary forachieving therapeutic effects.

Importantly, stimulation between pairs or groups of electrodes in theimplanted array or bundle of electrodes can be used to direct thestimulation field within a cluster of electrodes. The electrical fieldis focused between the electrodes used, and the current distribution isdependent on the resistance of the tissue. Current taking a detourbetween two electrodes becomes reduced, and thereby the current isfocused to the area between the electrodes. If electrodes present in theperiphery of the electrode cluster are used as a pole, a sub-group ofthe electrodes present within the cluster may be used as an oppositepole.

Neurons and in particular their axons are often oriented along a mainaxis. For example, the dendrites of “pyramid” neurons in cortex cerebriextend toward the surface of the cortex. Such neurons therefore areoriented to some extent along an axis that is parallel to the normal ofthe cortical surface. Another example of polarized neuronal structuresis neuronal pathways comprising axons connecting different regions inthe brain or spinal cord. The white matter of the central nervous systemcomprises a large number of axons often running in more or less parallelbundles. While for most parts the axis parallel to the bundles changelittle in orientation, the direction of the axons may change directionalong its path, such as when corticospinal pathways cross the midline inthe medulla. An additional example is peripheral nerves which comprisemultiple axons extending in the same main direction but close to thespinal cord may deviate from the main axis.

To initiate nerve impulses (action potentials) with electric stimulationof a neuron, the membrane potential of cell body or its axon has tobecome depolarized to the threshold of the action potential. For this tohappen during electrical stimulation, current has to pass into the cellin one area of the cell (which gets depolarized) and out from the cellin other areas (which gets hyperpolarized). Therefore, to initiate anerve impulse in a neuron, an electrical field directed along the mainaxis of the neuron is usually more effective (requires less current)than an electrical field directed transverse to the main axis of theneuron (Kandel, E. R. Schwartz, J. H. and Jessell, T. M. (2000)Principal of Neural Science, Fourth edition, McGraw-Hill Companies, Inc,New York, London, Tokyo, 1414 pages).

The present invention is based on the insight that stimulation betweenpairs or groups of electrodes spread out in the tissue can be used todirect the electrical field within a cluster of electrodes. Thedirection of the electrical field is here defined as the main directionof current between the electrodes within the cluster of electrodes. Incase the electrodes are divided into two groups wherein each electrodeof respective group has same potential the main current direction willbe from the group with positive potential to the group with negativepotential.

The disclosed invention is based on the insight that the electricalfield can be directed in different ways by stimulating between differentelectrodes or groups of electrodes in a cluster of electrodes spread outin the excitable tissue, and that this can be used to increase thespecificity of the stimulation and to reduce the energy consumption ofthe treatment.

In one embodiment of the invention, the positions of the individualimplanted electrodes spread out in the tissue are determined usingimaging techniques such as computer tomography. Stimulation ispreferably made either between electrodes from which therapeutic effectshave been obtained or between the electrodes that do not give rise toadverse effects as described above.

In another embodiment, the electrodes of the electrode pairs arepositioned in two different electrode clusters located close to neuronsoccupying two separate hemispheres of tissue or in such a way that theelectrical field obtained is directed along the main axis of neurons.

In yet another embodiment, wherein it is combined with the secondoptimization as defined above.

In one embodiment, one single electrode forms pairs with two or moreother electrodes.

In another embodiment, several pairs of electrodes are used forstimulation at the same time.

In another embodiment, one chosen pair of electrodes is used forstimulation consecutively after another pair of electrodes has been usedfor stimulation. In this way, a “wave” of stimulation may be achieved.

In one embodiment of the present invention, the implanted electrodes aredivided into two groups between which stimulation is made. In case theposition of the electrodes is known with respect to each other,stimulation can be applied between groups of neurons occupying twoseparate hemispheres of tissue such that current passed from eachelectrode will add to the current in the main direction from one groupto the other. By systematically exchanging electrodes between the twogroups, the effect of different directions of the electrical field canbe assessed with respect to the therapeutic effects and energyconsumption and the direction that produces an acceptable therapeuticeffect with the lowest energy consumption can be determined.Alternatively, the combination causing an optimal therapeutic effect atan acceptable energy expenditure is determined. Stimulation strength,frequency, pulse shape and duration are preferably held constant whilesearching for the optimal direction of the electrical field.

In another embodiment, structural data is obtained on the orientation ofnearby cells and axons from anatomical descriptions of the region ofinterest. By combining the structural data and data on the location ofthe active sites of the implanted electrodes, the two groups ofelectrodes that can be predicted to produce the most promising directionof the electrical field may be evaluated first in order to reduce thetime to find a therapeutic effect.

Optionally, data on preferred direction of the applied electrical fieldin same tissue in previous patients stored in a database is used toassign the electrodes to either of group 1 or group 2 such thatstimulation between the groups of electrodes results in thepredetermined main direction of the electrical field to be tested. Thetherapeutic effect and energy consumption for the tested orientation ofthe electrical field is stored in a data base. Since, as describedabove, there are inter-individual differences between patients and theelectrodes will not likely occupy identical sites in different patientsit may be necessary to fine tune the direction of the electrical fieldby reassigning some of the electrodes in the first of the two group tothe second group and vice versa to find the optimal assignment ofelectrodes into the two groups of electrodes. Stimulation strength,frequency, pulse shape and duration are preferably held constant whilesearching for the optimal direction of the electrical field.

According to a further embodiment, the set of implanted electrodescomprises electrodes which are located on the same physical entity. Theentity has e.g. a rod-like shape. The entity may be a foil. The entitymay be non-soluble or non-degradeable.

Importantly, an embodiment wherein a directed electrical field is usedfor stimulation may include one or more of the features discussed inthis application.

Furthermore, an embodiment wherein a directed electrical field is usedfor stimulation may be used to treat one or more of the medicalconditions discussed in this application.

According to one embodiment of the invention, the excitable tissue maybe neuronal tissue or endocrine tissue, the heart or the vascularsystem. The tissue may be human or animal tissue.

According to another embodiment of the invention, the neuronal tissuemay be brain tissue, spinal cord or periferal nerves.

Importantly, the present invention applies to grey and white matter inthe brain and spinal cord, as well as to peripheral nerves. This appliesto both electrodes implanted in target tissue as well as electrodesimplanted on the surface or nearby the target tissue, e. g. conventionalelectrodes used for spinal cord stimulation.

According to yet another embodiment of the invention, the brain tissuemay be selected from the group consisting of e.g. subthalamic nucleus(STN), globus pallidus interna (GPi), periaqueductal grey substance,periventricular grey, internal capsule, ventral posterolateral nucleus,thalamus, striatum, habenula, hypothalamus, basal nucleus of Meynert,cortical areas, brain stem, medial forebrain bundle, internal capsule,amygdala, hippocampus, septum, and ventral posteromedial nucleus.However, it is important to realize that any brain tissue may bestimulated and thus the present invention may be used to optimize thestimulation of these tissues.

The subthalamic nucleus (STN) and globus pallidus interna (GPi) arecommonly used sites for DBS treatment of Parkinson's disease. However,other sites, such as the caudal zona incerta and the pallidofugal fibersmedial to the STN, locomotor regions in the brain stem may also bestimulated in the treatment of Parkinson's disease.

In the case where the stimulation of brain tissue is for treating and/oralleviating nociceptive pain, the brain tissue may be structures thatare involved in pain modulation. Examples of such structures are theperiaqueductal grey substance, thalamus, brain stem structures such aslocus coerulius, raphe nuclei, cerebellum, dorsal column of the spinalcord, dorsal root ganglia, nucleus habenula, and periventricular grey.

In the case where the stimulation of brain tissue is for treating and/oralleviating neuropathic pain, the brain tissue may be the internalcapsule, ventral posterolateral nucleus, and ventral posteromedialnucleus.

The present invention may be used to optimize the stimulation of anyelectrically excitable tissue, e.g. peripheral nerves and innervatedtargets.

Thus, the present invention may be used to optimize the stimulation ofthe electrical conduction system of the heart, e.g. for the optimizationof the stimulation by a pacemaker. Furthermore, the present inventionmay be used to find a subset of electrodes causing the lowest energyconsumption for effective and reliable use in pacemaker therapy.

The present invention also applies to endocrine organs.

According to one embodiment of the invention, the endocrine tissue maybe selected from the group comprising pancreas, pituitary gland, andpineal gland.

Pancreatic tissue may be stimulated to treat and/or alleviate e.g.diabetes.

Thus, another example is to find the most effective way of regulatinginsulin production by selecting nerve fibers causing an increased gain(in the relation between insulin production to blood glucose levels,which is typically lowered in diabetes type 2) in the B-cells in theLangerhan's islet cells in the pancreas. In this example the signal fromthe patient should involve glucose measurements in order to assess thestimulation produced change in sensitivity (gain). It is known that oneof the functions of the vagus nerve is to mediate central commandsregulating the sensitivity in these endocrine cells. Since the vagusnerve is involved in regulation of many organs, via different nervefibers, it is an advantage to improve the selection of nerve fibersstimulated to those related to the disease treated. By implanting manyelectrodes in and around the vagus nerve, optionally in the pancreasitself, and then selecting the electrodes producing an increase inglucose sensitivity in the B-cells in the Langerhan's islet cells in thepancreas (i.e. increased gain in the relation between insulin productionand blood glucose levels), which is typically lowered in diabetes type2. Note that in this example the signal from the patient should involveglucose measurements in order to assess the stimulation produced changein sensitivity (gain).

The pituitary gland and hypothalamus may be stimulated to treat and/oralleviate e.g. blood pressure and body growth.

There are a number of other applications in the body where anadvantageous strategy could be to spread out biocompatible electrodes inand around the target and then select the most appropriate electrodes toreach therapeutic effects and/or save energy.

According to another embodiment, each group of electrodes is chosenrandomly. One advantage of this embodiment is that each electrode istested together with other electrodes which are randomly chosen. In thisway, unexpected effects relating to the concomittant stimulation of twoor more electrodes may be found.

Preferably, electrode groups may be used, in which the relative locationof the individual electrodes are known, such that it is known that theelectrodes which are located close to electrode X are electrodes Y, Zand W. This enables that the effect of stimulation within limitedlocations may be systematically explored, thus reducing the time neededto find electrodes which give rise to the desired therapeutic effect, ascompared to when the local distribution of the electrodes is unknown.

According to another embodiment, each group of electrodes is chosen byperforming the following steps of recording of an activity pattern inthe excitable tissue by each implanted electrode, optionally identifyingthe anatomical compartment or type of cells from which the electrode isrecording the activity pattern, comparing the recorded activity patternwith information stored in a database, and choosing the group ofelectrodes to be used for stimulation on the basis of a result of saidstep of comparing and/or optionally on the basis of the identifiedanatomical compartment.

The information stored in the database may comprise activity patternscoupled to the effect of stimulating cells or groups of cells whichexhibit the activity pattern. The information in the database may havebeen collected from many different patients, e.g. up to more than 1000patients. The activity patterns may be 2D diagrams where the neuronaldischarge frequency and time is presented on the X and Y axis,respectively. The effect of stimulation may be given on a scale from−100 to +100, where +100 signifies maximal therapeutic effect and −100maximal side effects, as disclosed above.

An advantage of this embodiment is that by using the database to predictthe electrodes which are most likely to give rise to the desiredtherapeutic effect when they are used for stimulation, a limited numberof electrodes may be used for the optimization of the final stimulationpattern. Preferably, the electrodes used for registration are not usedfor stimulation. The electrodes used for registration provideinformation regarding the anatomical locations in the target area thatis to be stimulated. Thus, according to one embodiment of the invention,stimulation is made through electrodes nearby the recording electrodesthat show the most promising activity pattern(s).

According to yet another embodiment of the invention, each group ofelectrodes is chosen by performing the following steps of recording ofan activity pattern in the excitable tissue by each implanted electrode,optionally identifying the anatomical compartment or type of cells fromwhich the electrode is recording the activity pattern, and choosing thegroup of electrodes to be used for stimulation on the basis of therecorded activity patterns and/or optionally on the basis of theidentified anatomical compartment.

It is well known that different cells or groups of cells (anatomicalcompartments) have different activity patterns. Different anatomicalcompartments have different characteristics and implications andconsequently play different roles in different diseases and disorders.By choosing the groups to be tested based on the assumed role andpotential implication of a certain anatomical compartment in thetreatment of a certain disease, the time used for the optimization ofthe stimulation pattern of the set of implanted electrodes may beshortened. In addition, by using the database to predict the electrodeswhich are most likely to give rise to the desired therapeutic effectwhen they are used for stimulation, a limited number of electrodes maybe used for the optimization of the final stimulation pattern.

According to a further embodiment of the present invention, the methodfurther comprises the following steps of coupling the anatomicalcompartment or type of cells with the information from the patient in adatabase, and coupling combinations of electrodes which stimulatecertain anatomical compartments or types of cells to the informationfrom the patient in a database. The documentation with respect toanatomical compartments can be done using e.g. CT or MRI imaging.

In this way, a database is established comprising information regardingthe anatomical compartments or types of cells and information about theeffect of stimulation of the anatomical compartments or types of cells.The database may also comprise information about e.g. energy consumptionand effective stimulation parameters such as e.g. frequency, amplitudeand wave shape. The database may later be used when determining thegroups which are to be tested when optimizing the stimulation pattern ofa set of implanted electrodes in a new patient. The information storedin the database may comprise activity patterns coupled to the effect ofstimulating cells or groups of cells which exhibit the activity pattern.The information in the database may have been collected from manydifferent patients, e.g. up to more than 1000 patients.

According to another embodiment of the invention, the method accordingto the present invention may also comprise the step of optimizing one ormore stimulation parameters for the use of the electrodes chosen to beincluded in the stimulation pattern in a stimulation treatment of thepatient, wherein said chosen electrodes are subjected to stimulationtests in which one or more stimulation parameters chosen from the groupcomprising the pulse width, the amplitude of the stimulation pulse, thestimulation strength, the stimulation frequency, the temporal pattern ofstimulation, the shape of the stimulation pulse, the polarity, and thestimulation type as to the degree of randomization, amplitudemodulation, frequency modulation are varied wherein information providedby the patient is registered for each test, wherein each parameter setis assigned a value related to said information, and wherein theparameter set having the most favorable assigned value, e. g. on theabove-mentioned scale from −100 to +100 is chosen to be used for thechosen electrodes during the stimulation treatment, or wherein said oneor more stimulation parameters also are used in the stimulation test ofthe second optimization step in view of energy consumption.

The stimulation strength influences the number of nerve cells in thevicinity of the stimulated electrode, and the frequency influences theimpulse frequency of the nerve cells.

Optionally, one or more parameters may be held constant while the otherparameters are varied. In one example the frequency is stabilized at 150Hz and the pulse duration at 200 μs, while varying the amplitude of thestimulation pulses from 0.1 to 10 volts.

According to another embodiment, said step of optimizing one or morestimulation parameters also or alternatively is performed for one ormore of the groups of electrodes, preferably all of the groups ofelectrodes, chosen from said certain number of electrodes from said setof implanted electrodes.

According to another embodiment of the invention, the method accordingto the present invention may also comprise the step of optimizing one ormore stimulation parameters for the use of the electrodes chosen to beincluded in the stimulation pattern in a stimulation treatment of thepatient, wherein said chosen electrodes are subjected to stimulationtests in which the burst mode, is varied wherein information provided bythe patient is registered for each test, wherein each parameter set isassigned a value related to said information, and wherein the parameterset having the most favorable assigned value is chosen to be used forthe chosen electrodes during the stimulation treatment, or wherein saidone or more stimulation parameters also are used in the stimulation testof the second optimization step in view of energy consumption accordingto claim 3.

According to another embodiment of the invention, one or more of theamplitude of the stimulation pulse, the stimulation frequency, and theshape of the stimulation pulse may be varied in each test.

According to another embodiment of the invention, each group ofelectrodes is chosen by performing the following steps of performingbrain scanning, MRI examination, CT examination, and/or ultrasoundexamination, identifying the anatomical compartments where the electrodeis located, and choosing the group of electrodes on the basis of thelocation of the electrodes.

By choosing the electrodes which are to be tested on the basis of theirphysical location as determined by a brain scan, an MRI examination, aCT examination and/or an ultrasound examination, the time used for theoptimization of the stimulation pattern of the set of implantedelectrodes may be shortened.

According to one embodiment of the invention, the number of electrodesin each group is 1-15, preferably 5-15. However, the number ofelectrodes included in each group may be dependent on the total numberof implanted electrodes, such that up to 50%, preferably 15-30%, morepreferably 20-25%, of the implanted electrodes are included in eachgroup. The number of electrodes included in each group may also be allimplanted electrodes except one or more.

According to another embodiment of the invention, the information fromthe patient is a response to the effect of the stimulation perceived bythe patient. Such effects may be related to anxiety, nausea, vertigo,dizziness, itch, anger, tiredness, and sleepiness.

This is especially advantageous, since it is the patient's actualperception of the stimulation that guides the selection of electrodeswhich are to be used in the treatment. In this way, the patient canactively take part in the selection of electrodes, which will be moretime efficient. Further, the patient will also feel that he/she has morecontrol of the test protocol of the test procedure, which may relieveanxiety.

The information may be feedback actively given by the patient in view ofa perceptual change of the patient's condition induced by the electricalstimulation.

According to another embodiment of the invention, the information fromthe patient is a value obtained by measuring a physiological,psychological, or pathological reaction of the patient. Examples of suchreactions are e.g. blood pressure, blood glucose level, transpiration,muscle activity, eye movements, and body movements.

In certain cases, it may be more advantageous to use a measurement of aphysiological, psychological, or pathological reaction of the patient inorder to achieve a more favorable selection of electrodes which are tobe used for the treatment. Such cases may be in patients who, due totheir disorder, are unable to communicate their perceptions, such as forlate stages of ALS, tetraplegic patients, severely depressed patients,and cognitively impaired patients. Other cases may involve conditions inwhich the effect of the stimulations is not perceived immediately by thepatient, but in which the effect may be predicted by measuring aphysiological, psychological, or pathological reaction of the patient,e.g. effects on depression can be deduced by tests measuring theresponse time, and memory impairments such as Alzheimer's disease can betested using simple recognition tests.

According to another embodiment of the invention, the information fromthe patient is a combination of a response to the effect of thestimulation perceived by the patient and a value obtained by measuring aphysiological, psychological, or pathological reaction of the patient.

According to one embodiment of the invention, the information from thepatient may be binary. In such a case, the patient may indicate if thestimulation gives an effect or not.

The information from the patient may also be analogue or comparative,e.g. “better than before”, “worse than before” or “same as before”.

According to another embodiment of the invention, the information fromthe patient may be given on a scale. One example of such a scale is a“visual analogue scale” (VAS).

According to one embodiment of the present invention, 10-50, preferably15-40, most preferably 20-35, different groups of electrodes arestimulated.

According to another embodiment, 3-50, preferably 10-40, most preferably20-35, different groups of electrodes are stimulated.

According to one embodiment of the invention, the information from thepatient may be provided by means of a joystick, a touch screen, a pad, acomputer mouse, and/or a trackball. In this way, the method may beadapted to the patient's own possibilities to provide information aboutthe effect of stimulation.

According to one embodiment of the invention, the information from thepatient may be provided by means of a device registering eye movements.Especially, devices registering eye movements, so called “eye trackers”,may be used. Such a device may be provided in special eyeglasses. Withsuch a device even an almost paralyzed patient may be able to providevoluntary information about the effect of the stimulation by controllinge.g. a cursor on a screen.

According to another embodiment of the invention, the method steps maybe preceded by a step in which the patient is allowed to get accustomedto the conditions and equipment utilized during the stimulation. Afterthis step or “training period”, the patient is accustomed to the deviceand to how it may be controlled. This is advantageous since the actualoptimization will take less time than if the patient were not familiarwith the procedure. In addition, the patient probably will feel morecomfortable in the situation when the procedure is known beforehand.

The patient and a care provider, such as e.g. a physician, may be in onelocation when the optimization of the stimulation pattern of the set ofimplanted electrodes is performed, and may be in contact with an expertin the field who may be in another location. The expert may follow theprocedure remotely, such as over the internet, and may provide guidanceand comments.

According to one embodiment of the invention, the stimulation and theprovision of information may be performed by the patient himself/herselfvia electronic connection with a practitioner/physician. Thus, a firstoptimization may be made under the supervision of a care provider and afine tuning of the optimization may be made by the patienthimself/herself, e.g. in his or her home. As the underlying diseaseconditions progress it may also be useful to tune the stimulationparameters over time. This may be advantageous since the patient neednot leave his or her home to go to a hospital to do the fine tuning ofthe stimulation. In addition, for certain conditions, such as e.g.depression, the full effect of stimulation of excitable tissue is notseen until after several weeks, and it is thus favorable if a gradualfine tuning of the stimulation may be performed over a longer period oftime by the patient in his or her home. This fine tuning may beperformed under the supervision of a care provider, e.g. by contact viae.g. the internet. Thus, there is no need for the patient to leavehis/her home in order to fine tune the stimulation. This procedure isalso cost saving for the care provider. The fine tuning may be limitedto certain electrodes, such that electrodes which were found to inducenegative effects when stimulated are excluded from the fine tuning step.The fine tuning may be limited between certain stimulation parameters.

A care provider may have the possibility to terminate the stimulation ifundesirable side effects occur.

In certain situations, a side effect may be diminished or abolished byfine tuning of the stimulation parameters, such as frequency, pulseshape, amplitude etc. Thus, if a side effect is detected, thestimulation parameters may be changed in order to maintain the positiveeffect on the symptoms of the treated disease or disorder, while theside effects are diminished or abolished.

According to one embodiment of the invention, the method may be followedon a screen device on which the implanted electrodes in the tissue aregraphically represented, and wherein the patient has the ability tostepwise/gradually scan said groups of electrodes to stimulate thetissue. The electrodes may be graphically represented on e. g. a touchsensitive screen, The electrodes which are used for the currentstimulation may be identified, e.g. by having a different colour,strength of the colour or by being denoted by a different symbol thanelectrodes which are not currently active. In this way, the location ofthe electrodes in the tissue is visualized. Thus, it may be easy to seealready tested electrodes.

For blind patients auditory or somatosensory cues may be used instead toprovide information on which electrodes are currently used.

Multivariate analysis may be used in order to identify whichcombinations of electrodes and/or which combinations of stimulationparameters give rise to the desired effect. In such a way, unexpectedelectrode combinations may be found.

According to a third aspect of the invention, the present inventionrelates to a method for treatment or alleviation of a disease orcondition by use of a set of electrodes whose stimulation pattern hasbeen optimized according to the method described above, wherein thedisease or condition is chosen from the group consisting of brain and/orspinal damage, lost functions, pain, Parkinson's disease, tremor, motordisorders, choreatic and other involuntary movements, memory disorders,Alzheimer's disease, degenerative diseases, epilepsy, mood disorders,aggression, anxiety, phobia, affect, sexual over-activity, impotence,eating disorders, sleep disorders, such as narcolepsy, attentiondisorders, stroke, damage of the brain, damage of the spinal cord,bladder disorders after spinal cord injury, bowel disorders after spinalcord injury, spasticity, somatosensory disorders, auditory disorders,visual disorders, and olfactory disorders.

Neurons may be stimulated to compensate for lost functions. E.g. spinalneurones may be directly stimulated to trigger movements after lostconnection with the brain or to trigger functions such as emptying ofbladder or bowel.

Pain relief may be provided by stimulation of analgesic brain stemcentres.

Relief or decrease of tremor and other motor symptoms in Parkinson'sdisease may be provided.

Relief or decrease of choreatic and other involuntary movements may beprovided by stimulation within the basal ganglia or associated nuclei.

Memory may be boosted by stimulation of cholinergic and/or monoaminergicnuclei in case of Alzheimer's disease or another degenerative disease.

Control of mood, aggression, anxiety, phobia, affect, sexualover-activity, impotence, and eating disturbances may be provided bystimulation of limbic centres or other brain areas.

Sleep disorders may be treated by stimulation of suitable targets inthalamus and brain stem that regulate sleep.

Attention disorders may be treated by stimulation of locus coerurleusand other monoaminergic structures.

Rehabilitation after stroke or damage of the brain and/or the spinalcord may be provided by stimulation of remaining connections in thecortex cerebri, in the spinal cord, or in descending motor pathways.

Re-establishment of control of spinal functions such as bladder andbowel emptying after spinal cord injury, may be provided by stimulatingrelevant parts of the spinal cord or peripheral nerves.

Control of spasticity may be provided by stimulation of inhibitorysupraspinal descending centers or appropriate cerebellar areas.

According to a fourth aspect of the present invention, a system foroptimization of the stimulation pattern of a set of implanted electrodesin excitable tissue of a patient and for treatment or alleviation of adisease or disorder with the method according to the present inventionis also provided. The system comprises a set of electrodes having theability to be implanted in excitable tissue of a patient, a stimulationdevice connected to said set of electrodes and having the ability tostimulate said excitable tissue via said set of electrodes, a firstcomputer program connected to the stimulation device and having theability to transform information provided by the patient to an assignedvalue for a tested group of electrodes, to calculate a total assignedvalue for each electrode, and to choose a preferred set of electrodes tobe used for stimulation treatment. The first computer program has theability to choose a group of electrodes from the set of implantedelectrodes and to instruct the stimulation device to stimulate thetissue through these electrodes. Alternatively, the first computerprogram has the ability to choose a set of nearby electrodes optimizedfor stimulation and to instruct the stimulation device to stimulate thetissue through these electrodes.

According to one embodiment of the invention, the system furthercomprises a recording device connected to said set of electrodes andhaving the ability to register an activity pattern in said excitabletissue, a second computer program connected to the recording device andto the first computer program, and a database connected to said firstcomputer program and to said second computer program. The secondcomputer program has the ability to compare information obtained fromthe recording device in view of the registered activity pattern in saidexcitable tissue with information in the database in the form ofpreviously registered activity patterns for several patients regardingthe effect of stimulation of the same or similar excitable tissue ofsaid several patients, to choose a collection of useful electrodes withthe basis on said comparison of activity patterns, and to transform theinformation about the chosen electrodes to the first computer program,wherein said first computer program also has the ability to transmit theinformation provided by the patient to the database for storage.

According to one embodiment of the invention, the set of implantedelectrodes may comprise a plurality of microelectrodes.

According to another embodiment of the invention, the set of implantedelectrodes may comprise electrodes which are located on differentphysical entities. Thus, the electrodes may be located on separateleads, i.e. they are not located on the same surface, plate or cylinder.

According to another embodiment of the invention, the system may furthercomprise a joystick, a touch screen, a pad, a computer mouse and/or atrackball, wherein the joystick, touch screen, pad, computer mouseand/or trackball is used by the patient to provide the first computerprogram with information.

According to one embodiment of the invention, the system may furthercomprise a device registering eye movements, wherein the deviceregistering eye movements is used by the patient to provide the firstcomputer program with information.

According to one embodiment of the invention, the system may furthercomprise a screen device on which the implanted electrodes in the tissueare graphically represented. The patient has the ability tostepwise/gradually scan said groups of electrodes to stimulate thetissue. This can be done by e.g. applying pressure on the symbols forthe respective electrodes to be stimulated. The electrodes which are tobe tested may be selected by moving a predetermined search field acrossa screen. The electrodes which are used for the current stimulation maybe identified, e.g. by having a different colour, strength of the colouror by being denoted by a different symbol than electrodes which are notcurrently active. In this way, the location of the electrodes in thetissue is visualized. Thus, it may be easy to see already testedelectrodes.

According to one embodiment of the invention, the system may furthercomprise conventional equipment for measuring the physiologicalreactions of the patients to the stimulation through the implantedelectrodes. Such equipment includes but is not limited toelectromyography (EMG) to record e.g. tremor, eye movements, involuntarymovements, or voluntary movements, conventional equipment for measuringskin blood flow such as Laser Doppler techniques, conventional equipmentfor measuring blood pressure, equipment for measuring blood glucoselevels, conventional multichannel equipment for electroencephalogram(EEG) to measure for example arousal, sleep cycles, brain states asdefined by the frequency of the EEG, epileptic brain activity.

The system may be adapted to the patient regarding e.g. the speed and/orsensitivity of the device for controlling and/or providing theinformation. For example, if a patient has shaky hands or suffers fromtremor, the sensitivity of the device may be set at a lower level sothat only voluntary movements will be registered. In this way,overstimulation due to involuntary movements may be avoided. Further, asafety arrangement may be provided, by which the stimulation by theimplanted electrodes is terminated if anything undesirable occurs duringthe stimulation, such as if the patient is affected by cramps, euphoriaor other undesired side effects. Alternatively, or additionally, a careprovider may have the possibility to terminate the stimulation ifundesirable side effects occur.

The system may be provided with a history function, such that thepatient and/or the care provider can identify which electrodes havealready been tested. In addition, the history function may also show arepresentation of the results of the information provided by thepatient.

The history function may be coupled to the screen, such that it ispossible to visualize the electrodes which have been tested earlierduring the procedure.

Selection of a preferred direction of the electrical field onstimulation can either be made by letting the computer systematicallytest the effect of different directions of the electrical field(accomplished as described above) while the patient provides feedback onthe therapeutic effects as described above for the different parametersor the patient can by manipulating e.g. a joystick or button that can beturned clockwise or anticlockwise indicate the direction(s) causing thebest therapeutic effects on a computer screen.

Optionally, the medically responsible person may operate the computer soas to scan through the different directions of the electrical fieldwhile the patient either indicates the therapeutic efficacy on acomputer screen by moving a cursor or a joystick or in any other way asdescribed above.

In cases where the patient is unable to indicate the therapeutic effect,a physiological measurement may be used instead as described above forassessments of the efficacy of different stimulation parameters.

The range of preferred directions of the electrical field is preferablystored in a data base along with data on selected electrodes andparameters of stimulation such as stimulation strength, pulse shape,frequency of stimulation, burst or tonic stimulation patterns andduration of stimulation.

By way of example, different embodiments of the present invention willnow be described with reference to the accompanying drawings, in which:

FIG. 1 shows a system according to the present invention comprising afirst computer program P1 and a stimulation device S which is capable ofstimulating electrodes 3 implanted in excitable tissue 2 of a human oran animal. The stimulation may be performed synchronously ornon-synchronously. Synchronous stimulation of all of the electrodes in agroup means that an electric pulse reaches all the electrodessimultaneously. During non-synchronous stimulation the stimulation ofthe different electrodes does not take place simultaneously. One exampleis when the different electrodes in a group are consecutively stimulatedduring the test cycle. The first computer program P1 chooses a group ofelectrodes from the set of implanted electrodes 3 and instructs astimulation device S to stimulate the tissue through these electrodes. Aresponse from the patient is registered and this information is providedto the first computer program P1. The response provided from the patientis transformed by the first computer program P1 to a value which isassigned to all the electrodes of the group. This procedure is repeatedfor one or more different groups of electrodes from the set of implantedelectrodes 3. When all groups have been tested, each individualelectrode has been used for stimulation at least three times, preferablyat least 10 times. The total assigned value is calculated for eachelectrode by the first computer program P1 and electrodes having a totalassigned value exceeding a predetermined value are chosen to be includedin the final stimulation pattern. The total assigned value may be anaverage value. The first computer program P1 provides the stimulationdevice S with the final stimulation pattern. Optionally, the firstcomputer program can be externally controlled, via e.g. the internet.

FIG. 2 shows a system according to the present invention comprising afirst computer program P1, a stimulation device S which is capable ofstimulating electrodes 3 implanted in excitable tissue 2, a registrationdevice R capable of registering signals transmitted from the excitabletissue 2 through the electrodes 3, a second computer program P2 and adatabase DB. The stimulation may be performed synchronously ornon-synchronously. The registration device R records signals transmittedfrom the excitable tissue 2 through the electrodes 3 and provides asecond computer program P2 with the information. The second computerprogram P2 compares the information received with information stored inthe database DB. In the database DB information regarding previouslyrecorded activity patterns from excitable tissue has been coupled withinformation regarding the effect of stimulation of the same tissue. Inaddition, the database may comprise data regarding the stimulationparameters, e.g. amplitude and frequency. Based on the recorded activitypatterns and the information retrieved from the database DB, the secondcomputer program P2 chooses a collection of electrodes and transmitsthis information to the first computer program P1. From the collectionof electrodes the first computer program P1 chooses a group ofelectrodes from the set of implanted electrodes 3 and instructs astimulation device S to stimulate the tissue through these electrodes. Aresponse from the patient is registered and this information is providedto the first computer program P1. The response provided from the patientis transformed by the first computer program P1 to a value which isassigned to all the electrodes of the group. This procedure is repeatedfor one or more different groups of electrodes from the set of implantedelectrodes 3. When all groups have been tested, each individualelectrode has been used for stimulation at least two times, preferablyat least three times, most preferably at least 10 times. The totalassigned value is calculated for each electrode by the first computerprogram P1 and electrodes having a total assigned value exceeding apredetermined value are chosen to be included in the final stimulationpattern. The total assigned value may be an average value. The firstcomputer program P1 provides the stimulation device S with the finalstimulation pattern. Optionally the first computer program can beexternally controlled. Optionally, new information regarding therecorded activity pattern coupled to a response in the patient may betransmitted to the database DB and stored. The database may optionallyalso include stimulation data, such as values for different parameters.The computer program 1 and the computer program 2 may be the samecomputer program.

In the method and a system according to the present invention, mainlythe patient is in charge and controls the events leading to theoptimization of the stimulation pattern of a set of implanted electrodesin excitable tissue of the patient. Importantly, the method and systemis user friendly, as mainly the patient has control by simplecommunication of stimulation effect to a computer. The system, bykeeping track of the electrodes which have been stimulated and theoutcome, greatly simplifies the task for the patient to optimize thestimulation when further fine tuning the stimulation parameters.

The method according to the present invention is performed on a set ofelectrodes which have been implanted in human or animal excitabletissue, neuronal tissue, e.g. the brain or the spinal cord, or endocrinetissue, by use of conventional implantation techniques. The neuronaltissue may be specific nuclei or subnuclei but can also be neuralpathways between different areas of grey substance. In the treatment ofe.g. Parkinson's disease, the electrodes may be implanted into thesubthalamic nucleus. When the electrodes are used for treating a paincondition, they may be implanted into the periaqueductal grey substanceor thalamus.

The three dimensional location of the selected group of electrodes to beused for the stimulation of the neuronal tissue is of great importancewith a view to achieving an optimal or satisfactory stimulation patternand thereby a satisfactory treatment of a specific disease conditioncoupled to said neuronal tissue.

It is known that there are individual differences regarding exactlywhich part of an excitable tissue gives the desired effect whenstimulated by implanted electrodes. Thus, there is a need to optimizewhich electrodes are used for stimulation in each individual patient.However, promising starting points may be found by testing in animals.

The method according to the present invention may be used to determinewhich of several implanted individual electrodes in a bundle or arraygive a satisfactory effect when used to stimulate the neuronal tissueinto which they have been implanted. An implanted array or bundle ofmultielectrodes may comprise from 10 and up to several hundreds orthousands or more even more single individual electrodes which can beused to stimulate the excitable tissue. Most often a multichannelelectrode comprises 16 to 64 electrodes. In certain cases, amultichannel electrode may comprise up to 128 electrodes, such as 16 to64, e. g. 32. This depends at least partly of the size of the targettissue.

It is important to understand that one specific individual electrode maygive rise to a positive effect when stimulated alone. A specificelectrode may also give rise to a negative effect or to no effect at allwhen stimulated alone. A specific electrode may also give rise to apositive effect only when stimulated together with one or moreindividual electrodes. A specific electrode may also give rise to anenhanced positive effect when stimulated together with one or moreindividual electrodes.

With a view to determining the optimal combination of electrodes tostimulate, a first group or cluster of a certain number of electrodes ischosen from the implanted set of electrodes for a first stimulationtest. When the chosen electrodes are activated, i.e. electricallystimulates the neuronal tissue that surrounds the chosen electrodes, thepatient tested or treated experiences a certain change in the symptomsof his or her underlying disease condition if one or more of thestimulated electrodes in said first group is correctly located in theneuronal tissue. Otherwise, no change or an adverse effect isexperienced. Such adverse effect may be involuntary movements or moodchanges. A long term adverse effect may the damage of neuronal tissue,without any positive effect regarding the condition to be treated.

Alternatively, a physiological, psychological or pathological reactionof the patient may be measured.

Feedback of the patient's experienced or perceptual change in symptomsis then mediated directly from the patient to the computer program, thecomputer database, and/or to the operator. This feedback or informationmay be given or delivered in several different ways, depending on e.g.the patient's health condition and ability to communicate the feedback.Inter alia, the patient may deliver this information by purely physicalactions, such as talking, blinking, waving, movement of a certain bodypart etc., or by use of technical equipment (pressing a button, via acomputer pad, touch screen, joystick, a touch screen, a pad a computermouse, a trackball etc. Alternatively, the feedback may be delivered viameasurement of physiological, psychological, or pathological parameters,such as blood pressure, pulse, and brain activity by use of instrumentsattached to the patient's body. Combinations of one or more of theabove-listed ways of obtaining the feedback from the patient may also beused.

Optionally, a training period may precede the optimization of thestimulation pattern of the set of implanted electrodes.

In the case where the patient is an animal one important differencedifference is that cognitive or perceptual changes have to be inferredindirectly, since animals cannot express the changes verbally.

It is of importance that the feedback coupled to the change of symptomsexperienced is delivered by the patient itself, i.e. not the physician,doctor, nurse, medical practitioner or anyone else, who otherwise issupposed to deliver information regarding change of symptoms inconventional methods in this area. The main reason for this is that thereliability/validity of the optimization method may be substantiallyincreased when the feedback origins directly from the patient who issubjected to the stimulation test. Other advantages with acquiring suchfeedback or input directly from the patient are that in the case oftreatment of symptoms, especially treatment of pain, it is moreeffective if the information is derived from the patient directly. Inaddition, it is more time efficient and an effective stimulation patternthat is “good enough” may be found in less time.

In one embodiment of the present invention, when the patient providessuch information, i.e. when signaling the change in symptoms, theexperienced change of symptoms in question is graduated, e.g. with aview to mediating if the change is minor or major. The way of graduationof the feedback signal depends on the patient's health condition andability to communicate as well as on the condition or disorder which istreated. A graduated scale may be used, e.g. with a score interval of1-10. In another embodiment a continuous scale may be used, such as theVAS (visual analog scale) pain scale. For example, the VAS may be usedto identify the effect of stimulation in patients suffering from pain.The scale may comprise a positive and a negative scale in order for thepatient to indicate positive as well as negative effects. The feedbacksignal may also be binary. Any other kind of graduation means and scaleintervals may be used, such as a electronic scale on a computer screenor screen of a laptop or a smartphone. Thus, all of the electrodes insaid first group of electrodes are assigned a certain value, i.e. areweighted, in relation to the feedback given by the patient.

After the first stimulation step a second stimulation step is performed,wherein a second group of a certain number of electrodes is chosen fromsaid set of implanted electrodes, and this second group of electrodes issubjected to a similar stimulation test as those in the first group, andall of the electrodes therein are assigned a certain value in acorresponding way. The number of electrodes in the second group may bedifferent from the number of electrodes in the first group, and may alsocomprise one or more of the electrodes tested in the first group.

Thereafter, a third stimulation step is performed, wherein a third groupof a certain number of electrodes may be chosen from said set ofimplanted electrodes, and the above-disclosed method steps are repeated.

The stimulation step may be performed a large number of times. Typically10-50 groups of electrodes, preferably 15-40 groups of electrodes, arestimulated.

In one particularly preferred embodiment 20-35 groups of electrodes aresubjected to the stimulation step. Each group of electrodes may contain1-15, preferably 5-15, and most preferably 3-7, electrodes.

Typically, 20% of the total number implanted electrodes are used in eachgroup which is used for stimulation. Every single electrode is tested atleast 3 times, preferably 5 times, more preferably at least 10-15 times.

The electrodes in the total set of electrodes may belong to more thanone of the groups of electrodes stimulated and are specifically indexedfor that purpose. This means that different values for a specificelectrode may be obtained during the different stimulation steps. Thus,combinations of electrodes which give rise to an optimal effect for thepatient may be found. All of the values of the electrodes in the groupsof electrodes that have been subjected to the stimulation step arerecorded by a recording device R and are stored in a computer (data)program P2/P1 or a database (DB). The computer keeps track of theeffects of all electrodes used.

If one specific electrode is associated with a negative effect in all orin a majority of the tests, such as a low degree of effect on thecondition or disease which is treated, or such as a side effect, thegroups may be tested again without this specific electrode.

When a group is tested, the stimulation parameters are set at low levelsand may then gradually be increased. Especially, the values of thestimulation parameters may gradually be increased in order to accustomthe patient to the stimulation. This is advantageous, since the patientis then gradually accustomed to the stimulation. In addition, a level atwhich the stimulation gives rise to the desired effect, but at which thestimulation does not give rise to any side effects, may be identified.If the method is preceded by an additional step of stimulating allelectrodes at once while increasing the stimulation strength, the abovementioned procedure may be excluded, since the patient is alreadyaccustomed to the procedure.

The frequency used for stimulation is preferably between 130 and 160 Hz.However, for certain applications, the frequency may be lower than 130Hz, such as 100 Hz or even lower. For other application, the frequencymay be as high as 20 kHz. In one embodiment, a fixed frequency value ischosen for the stimulation test.

The amplitude used for stimulation is between 0.1 and 10 V, preferablybelow 2 V. For a single electrode, the desired effect is achieved up toa certain amplitude, whereafter an increase in the amplitude may giverise to side effects such as injury of the tissue. During stimulationtests, the amplitude may be varied while the frequency is kept constant.

Preferably, the shape of the pulse wave is charge balanced, such thatthe current of negative ions to the electrode equals the current ofpositive ions to the electrode. If the pulse wave is not balanced, apolarity is accumulated at the electrode interface with the tissue,which may lead to ineffective stimulation.

Alternatively, but less preferred, the polarity of the stimulatingelectrode may be negative during the stimulation pulse, such that thestimulation originates from a cathode. In such a case, an electricalvoltage is achieved at the electrode interface with the tissue, which isallowed to decay before another stimulation pulse is emitted. It is ofimportance that a stimulation takes place between a reference electrodeand implanted electrodes or between the implanted electrodes, as thecircuit has to be closed.

When all of the stimulation steps have been performed, the totalassigned value for each electrode is determined by first adding theseparate values assigned during the stimulation steps and thencalculating the average value or median value which is used for thesubsequent comparison between the potentially useful electrodes. In oneembodiment the mean values and/or median values are updated during thetests performed, i.e. not only after the tests have been finalized. Thiscalculation may be automatically performed by use of the above-mentionedcomputer P1/P2. Thereafter, electrodes having a total assigned valueexceeding a predetermined limit value, i.e. providing an acceptabletherapeutic effect, as defined above, are generally chosen for thesubsequent treatment step. Correspondingly, the electrodes having thelowest total assigned value are generally deemed to not be useful. Insome cases the electrodes having the highest total assigned values maybe further separated into different groups and further stimulation testsmay be performed with a view to finding the “best of the best”electrodes for the intended purpose. In some cases the electrodes havingthe highest total assigned values or all the electrodes that have atotal assigned values that is above a predetermined limit may be furtherseparated into different groups and further stimulation tests may beperformed with a view to finding a group of electrodes that, when usedfor stimulation, give rise to the desired effect with the lowest energyconsumption. This is especially advantageous, since this will prolongnot only the lifespan of the battery, but may also prolong the life timeof the electrodes themselves depending on the materials of theelectrodes. In addition, the risk of damaging the tissue surrounding theelectrodes is reduced. Furthermore, the risk of also giving rise tonegative side effects is also reduced.

As stated above, generally the electrodes having the highest score areselected, but in some situations electrodes with a medium or even lowscore may be selected if they add positively to the therapeutic effect.This is the case when the therapeutic effect not is good enough with asmaller amount of electrodes. However, the expression “good enough” issubjective, and therefore the physician should decide whether there arereasons to increase the amount of electrodes with electrodes givingmoderate or weakly positive contributions.

The total number of electrodes used for the stimulation, the totalnumber of groups of electrodes, as well as the total number ofelectrodes in each group, is dependent on the underlying diseasecondition in question, the implantation area in the soft tissue, and thetype and size of the microelectrode.

Any kind of electrode may be used. It is preferred to usemicroelectrodes that are spread out in and around the target tissue.

Any kind of electrode used for DBS may be used, preferablymicroelectrodes, that are physically separated and spread out in andaround the target tissue.

Importantly, the electrodes used may be separate stimulation points,which is not the same as several electrodes located on the sameconstruct. The difference is that tissue surrounds each electrode ifthey are physically separated in the tissue which allows tissue betweenthe electrodes to be stimulated. This is not the case when electrodesare grouped together on the same physical entity. Electrodes currentlyused for DBS have many separate electrodes (contact points/active sites)on one physical entity. Such contact points will have contact with thetissue only on the side exposed to the tissue. Contact points/activesites located on physically separated entities such as microelectrodesthat have been spread in the tissue will be surrounded by tissue andsuch electrodes may thus be used to stimulate tissue which is betweentwo or more contact points/active sites.

In certain cases, larger or conventional DBS electrodes may be used.

When the electrodes having the most interesting effects, normally thehighest total assigned values, average values or median values, havebeen determined, the spatial localization of these is thereby also knownto the extent that it may be concluded that these electrodes are locatedin the desired brain tissue. It may be the case that the best effect isobtained from stimulation outside the nuclei, e.g. by stimulation ofaxons in the white substance. Thereby, no imaging step, like inconventional methods with a view to localizing the effective electrodesin the neuronal tissue, is required, which is an advantage. However, inorder to update the database which is used to predict the best positionsin subsequent patients, it is an advantage to determine the location ofthe electrodes using imaging techniques, such as e.g. CT and MRI. Thecontinuous updating of such a database from more and more patients willlikely facilitate the above described selection of the most effectiveelectrodes and also to provide guidance to the neurosurgeon as to theoptimal locations in the tissue to implant electrodes and to moreexactly and accurately focus on the nuclei and/or subcompartments withinnuclei and/or the precise nerve cells in question coupled to theunderlying disease condition to treat or from which optimal therapeuticeffects can be predicted.

The electrodes chosen in the method according to the present inventionmay be chosen by a computer P1, randomly or semi-randomly, or by theoperator. The operator can be the patient, the animal or a responsibleperson, e.g. a care provider, conveying the instructions from thepatient.

With a view to further facilitating the choice of effective electrodeswhich have been implanted in e. g. a human neuronal tissue for thestimulation of a specific nerve cell or nucleus, a predetermination stepmay be performed before the initiation of the optimization methodaccording to the present invention. Said predetermination step may bebased on data obtained during several tests of implanted electrodes inup to thousands or more patients in view of the specific activitypattern, sometimes also called firing pattern, each cell type produces.This data may be stored in a database DB. By referring to this database,the electrodes which are most likely to give rise to a good effect whenused for stimulation of excitable tissue may be predicted. This willmake the method less time consuming. Thus, this determination step mayalso be regarded to include the step of “listening” to the specific celltype. An implanted electrode may be used for stimulation of the neuronaltissue located in its proximity. However, the same electrode, or anotherelectrode fixated to said electrode, may also be used to record from theneuronal tissue located in its proximity. An advantage of using oneelectrode for stimulation and another electrode for recording is thatthe properties relating to both of these activities may be optimized.For example, electrodes suitable for ejecting currents often need tohave a relatively large uninsulated surface area to cause effectivestimulation of nearby neurons, whereas electrodes used for recordingsfrom single neurons should have a relatively small uninsulated surfacearea. When the electrode is small enough, such a recording may beconsidered to originate from one single cell or a few single cells. Moreprecisely, when an electrode is implanted in such a way that it reachesa specific nerve cell, the electrical signals from the cell can berepresented in a specific two-dimensional diagram, also called anactivity pattern, in an extracorporeal recording device R. The twodimensions of the diagram include time on one axis and occurrence ofnerve cell impulses on the other axis. Further, a specific sound mayalso be heard by the operator. The form of the diagram acts as a kind offingerprint for the cell type in question. Collecting data for all kindsof cell types gives a complete bank of activity patterns, andmeasurements from a large number of persons give a reliable averageactivity pattern coupled to efficacy data, i.e. to the effect ofstimulating such a cell. Thus, after collecting such data from severalpatients suffering from a certain condition and which are treated byelectrical stimulation, predictive data concerning the effect ofstimulating a cell or cells of a certain kind having a certain activitypattern is known.

In one embodiment of the present invention, such electrodes whichaccording to the collected data stimulate cells that are likely to giverise to a positive effect when stimulated, are chosen to be included inthe groups which are used for finding the most optimal stimulationpattern. In other words, electrodes chosen in this way are likely togive rise to a positive effect when used for stimulation of theexcitable tissue. The chosen electrodes are then used for stimulationand the information obtained from the patient is recorded as describedabove. Thus, according to one embodiment, the present invention alsocomprises the steps of recording the activity pattern of each implantedelectrode of a patient, optionally identifying the type of cell or cellsfrom which the electrode is recording the activity pattern, and choosingthe electrode groups based on the recorded activity patterns.

For choosing the electrodes which are to be used in the stimulation, twosets of electrodes may be used. The first set comprises electrodes whichare used for recording signals from the neuronal tissue and the secondset of electrodes comprises electrodes which may be used forstimulation. Each electrode belonging to the second set of electrodesmay have an electrode from the first set fixated to it. In this way, thesignals recorded from the first electrode may be used to determine the(approximate) location of the electrode to which it is fixated, i.e. todetermine the electrodes which can be used for stimulation.Alternatively, the electrodes belonging to the first set are not fixatedto electrodes belonging to the second set, but arranged in such a waythat, when implanted, an electrode from the first set is implanted inclose proximity to an electrode belonging to the second set. In thisway, different electrode pairs can be identified and suitable electrodesbelonging to the second set may be selected by recording from acorresponding electrode belonging to the first set.

Preferably, the electrodes used for registration are not used forstimulation. The electrodes used for registration provide informationregarding the anatomical locations in the target area that is to bestimulated. Thus, according to one embodiment of the invention,stimulation is made through electrodes nearby the recording electrodesthat show the most promising activity pattern(s).

In addition, the above mentioned method of recording the firing patternfrom cells located in the proximity of the implanted electrodes may beused to exclude from the groups to be tested electrodes which have beenidentified as recording from/stimulating cells which give rise tonegative effects. This further optimizes the method according to thepresent invention.

When the three dimensional electrode location giving the optimalstimulation pattern for the treatment of a certain disease conditioncoupled to certain tissue has been determined, the treatment and energyconsumption may be further improved by adjusting such parameters as thepulse width, the amplitude, the stimulation strength, the temporalpattern of stimulation, the shape of the individual stimulation pulse,the polarity, the stimulation type (randomized or semi-randomized,sequential), and the frequency and/or by use of a modulated currencyfield, e.g. by letting the amplitude of the stimulation pulse vary overtime. The stimulation may also be frequency modulated over time orapplied as short lasting high frequency bursts interspersed with lowerstimulation frequencies.

In one embodiment the method according to the present invention alsoincludes the additional step of optimizing the energy consumption whileachieving an acceptable therapeutic effect. The values of thestimulation parameters, preferably one or more of the followingparameters: the amplitude, the wave shape of the electrical pulse (suchas e.g. sinus-formed and square-formed), the pulse length, and thefrequency used during the stimulation, may be optimized. This can beaccomplished by the stimulation of the chosen electrode set repeatedtimes at different values of these parameters. E.g., in a first testseries the stimulation strength and the wave shape may be held constantwhile the frequency is varied at different values. In a second testseries the stimulation strength and the frequency may be held constantwhile the wave shape is varied in different ways, and in a third testseries the wave shape and the frequency are held constant while thestimulation strength (either voltage or current intensity) is varied atdifferent values. In a further version, two of these three parametersare varied during the test while one of them is held constant. Theamount of different values tested during each test is not restricted,but normally up to 5 different values of each parameter are tested. Inanother version each one of said parameters may be varied according to asliding scale. The therapeutic effect is monitored (e.g. throughfeedback from the patient as previously described) and the energyconsumption is recorded. The energy consumption may be transformed intoa scale similar to the scale for registering the therapeutic effect.

Other examples of parameters which may optimized comprise the pulsewidth, the stimulation strength, the shape of the stimulation pulse, thepolarity, the stimulation type as to the degree of randomization and thetemporal pattern of stimulation, e.g. periods of higher frequencyfollowed by lower frequencies or quisence as when burst stimulation isused, wherein the internal frequency of pulses in the burst is higherthan the frequency of the bursts. One example is to use bursts with 3-10pulses, internal frequency exceeding 200 Hz wherein the bursts areseparated by a period of less frequent stimulation. Another pattern isto use amplitude modulation or frequency modulation. In the first caseamplitude modulation means that the pulse amplitude (either voltage orcurrent intensity) is varied over a certain time cycle between definedvalues. Frequency modulation means that the frequency is varied in sameway. The modulation may be e.g. sinusoidal variation of pulse amplitudeor frequency.

The energy consumption of each pulse can be calculated by a personskilled in the art given that the current and voltage is measured. Giventhat the voltage and current do not change significantly during the timeinterval measured, the energy consumption in each pulse may becalculated as absolute voltage×absolute current×time interval of thepulse. A measurement of the current and voltage of each pulse and thetotal number of pulses is in this case therefore enough for calculationa value for the energy consumption during each test series. In caseswhere the voltage and current changes during the pulse such as for e.g.a sinusoidal pulse, the energy consumption in each pulse may becalculated as the integral of the absolute (voltage×current) over time,i.e.∫_(t) ₁ ^(t) ² u(t)i(t)dtwhere u(t) is the voltage at time t and i(t) is the current at time t,and where t₁ denotes time of onset of the pulse and t₂ denotes the endof the pulse.

The energy consumption may be calculated as the energy consumption ineach pulse multiplied with the total number of pulses in the test. Thetotal energy consumption of the treatment will also include energyconsumption in the electronics and battery used to stimulate the tissue.

The tested group of electrodes is assigned a value based on thetherapeutic effect and on the energy consumption.

The assigned value may be a function of the therapeutic effect and theenergy consumption.

The therapeutic effect and the energy consumption may be given differentweight when assigning the value. The assigned value can be written as

${k\left( {{therapeutic}\mspace{14mu}{effect}} \right)} + \frac{m}{{energy}\mspace{14mu}{consumption}}$wherein k and m are predetermined constants.

In order to assign a value to a tested group, the therapeutic effect mayhave to be above a certain predetermined threshold and/or the energyconsumption may have to be below a certain predetermined threshold.Thus, if a certain set of stimulation parameters does not give anacceptable therapeutic effect, then m/(energy consumption)=0.

When the parameter tests have been performed and a value has beenassigned for each set of parameter values, the parameter set with thehighest value, total value, average value or median value, is chosen forthe subsequent stimulation treatment of the patient with the chosen setof electrodes.

Reducing the energy consumption is desired, since this will lead to alonger lifespan of the battery of the stimulation device connected tothe implanted electrodes. In most cases, the battery is implanted underthe chest of the patient and thus a battery change always involves asurgical procedure. By extending the lifespan of the battery, the timeinterval between these procedures is prolonged. In case rechargablebatteries are used longer time periods in between recharging can beobtained which is more convinient for the patient. Furthermore, thepresent invention, by reducing the energy demand, will also allowsmaller batteries, which today make up a large fraction of theelectronics. This will open up for smaller electronic implants that canbe placed closer to the target tissue. Long connecting cables to theelectronics, which can cause discomfort to the patient, may thus beavoided. Also, the size of the electronics of the stimulator depends alot on the size of the battery. So if the energy consumption can bereduced the battery can be reduced in size and therefore also thestimulating device.

In addition, lower currents emitted from the implanted electrodes andtherefore also lower energy consumption will also lead to a reduced riskof damaging the tissue surrounding the electrodes. A lower energyconsumption will also cause less heat dissipation from the electrodesand electronics which is beneficial for the tissue around the electrodesand electronics. Lower currents emitted from the implanted electrodesand therefore also lower energy consumption may lead to a reduced riskof the stimulation resulting in unwanted side effects, i.e. stimulationof neurons which do not contribute (or which have a negative effect onthe therapeutic effect) to the desired effect may be avoided or reduced.Thus, the stimulation may be more targeted to neurons which whenstimulated contribute to the desired effect.

The main purpose of optimizing the energy consumption is to maintainsatisfactory stimulation treatment results, while at the same time theenergy consumption is reduced. This purpose may be fulfilled in severaldifferent ways.

First, the optimization of the stimulation pattern of implantedelectrodes disclosed throughout the application text above leads to theuse of a lower amount of electrodes for obtaining the same stimulationresult. Thus, reducing the group of implanted electrodes to a sub-groupof electrodes which are used for stimulation still providingsatisfactory results will as such significantly reduce the energyexpenditure.

Second, the design of the electrodes may be adapted to the treatment ofthe tissue in question. Different effective electrode designs andstructures are disclosed in the patent literature. However, thewell-known problem of the formation of kill zones in the tissue volumesurrounding the electrodes has now been observed to occur in particularwhen large electrodes are used (Thelin J, Jörntell H, Psouni E, GarwiczM, Schouenborg J, Danielsen N, Linsmeier CE. Implant size and fixationmode strongly influence tissue reactions in the CNS. PLoS One. 2011 Jan.26; 6(1):e16267).

Third, as also discussed above, the treatment and the energy consumptionmay be further improved by adjusting parameters such as the pulse width,the amplitude, the stimulation strength, the temporal pattern ofstimulation, the shape of the individual stimulation pulse, thepolarity, the stimulation type (randomized or semi-randomized,sequential), and the frequency and/or by use of a modulated currentfield, e.g. by letting the amplitude of the stimulation pulse vary overtime. The stimulation may also be frequency modulated over time orapplied as short lasting high frequency bursts interspersed with lowerstimulation frequencies.

Fourth, the stimulation can be arranged to be controlled by the patientonly, i.e. in such a way that stimulation only is performed when reallyrequired. Thereby, no unnecessary energy consuming stimulation isperformed.

In one embodiment the method according to the present invention alsoincludes the complementary steps of optimizing certain stimulationparameters with an ultimate view to improving the result of thestimulation treatment of patients.

In a first version of this embodiment, the following applies. When thepreferred electrodes have been selected according to the inventivemethod, the stimulation treatment may be further improved by optimizingthe values of the stimulation parameters, preferably one or more of thefollowing parameters: the amplitude, the wave shape of the electricalpulse (such as e.g. sinus-formed and square-formed), the pulse durationand the frequency used during the stimulation. This can be accomplishedby the stimulation of the chosen electrode set repeated times atdifferent values of these parameters. E.g., in a first test series theamplitude, the wave shape, and the pulse duration may be held constantwhile the frequency is varied at different values. In a second testseries the amplitude, the pulse duration, and the frequency may be heldconstant while the wave shape is varied in different ways. In a thirdtest series the wave shape, the pulse duration, and the frequency areheld constant while the amplitude is varied at different values. In afourt test the amplitude, the wave shape and the frequency may be heldconstant while the pulse duration is varied at different values. In afurther version, two or three of these four parameters are varied duringthe test while the other(s) are/is held constant. The amount ofdifferent values tested during each test is not restricted, but normallyup to 5 different values of each parameter are tested. In anotherversion each one of said parameters may be varied according to a slidingscale. The values are chosen from feedback from the patient, who willsignal when the effect is better or worse when the amplitude isincreased or decreased, or when the frequency is increased or decreasedetc. By adjustment of a sliding scale the parameter for stimulation ofthe intended group of electrodes may be tuned.

For each test, the patient provides information or feedback of theperception of the stimulation in the same way as described above. Whenthe parameter tests have been performed and a value has been assignedfor each set of parameter values, the parameter set with the highestvalue, total value, average value or median value, is chosen for thesubsequent stimulation treatment of the patient with the chosen set ofelectrodes. In such a way, both the electrode set used for thestimulation and the stimulation parameters are improved.

In a second version of this embodiment, the following applies. Theparameter value variation tests disclosed above may be performed in themethod according to the present invention in connection with thestimulation test of each one of one or more of the groups of electrodes,wherein each electrode in each group is assigned a value related to theinformation or feedback provided by the patient. In addition, the energyconsumption may be recorded and used as described above when assigning avalue to the tested group of electrodes.

Thus, instead of just one stimulation test, i.e. one set of parameters,for each group of electrodes as in the inventive method, severalstimulation tests with variations of the four above-mentioned parametersas disclosed above are performed for each group of electrodes. In such away, a preferred stimulation parameter set for each group of electrodesstimulated is obtained. When all of the different groups of electrodeshave been tested and the electrodes having the highest assigned values,total values, average values or median values, have been chosen, theparameter values coupled to the assigned values are checked and the bestones are chosen for each individual electrode in the subsequentstimulation treatment. Further, the parameter variation values testedmay differ for the different electrode groups tested. In this case,known mathematical and statistical methods, such as e.g. multivariateanalysis, are used to identify the optimal parameter values.

The embodiments involving the parameter value variation tests is moretime-consuming and demanding for the patient, since these embodimentsrequire that the patient becomes subjected to more tests compared towhen the inventive method is performed at constant parameter valuesthroughout the stimulation tests. The use of the parameter valuevariation tests should therefore be balanced with the curing and reliefeffects obtained for the patient due to this parameter optimization.

In another embodiment further of the above listed parameters, such asstimulation polarity, stimulation strength, and temporal pattern ofstimulation, may be varied in the parameter value variation tests inaddition to or instead of the four above-mentioned parameters.

In another embodiment of the invention, stimulation parameters arechosen so that an electrical field is created between the electrodesused for the stimulation, wherein the electrical field has a directionwhich allows the neurons located in the directed electrical field to bestimulated. An advantage of this embodiment is that less energy isneeded in order to stimulate the targeted neurons when the electricalfield is directed along the main axis of these neurons, as explainedabove. This may lead to a more specific stimulation, reducing the risksof side effects.

In one embodiment of the invention, the chosen parameters are alsostored in the database and may thus be used to choose parameters whichare more likely to result in the desired therapeutic effect. This willfurther contribute to shorten the time needed to optimize thestimulation.

In one specific embodiment of the invention, the patient controls theselection of the electrodes using for example an interactive screen orjoystick to be moved in a search field. A search field in this contextis a sub-area of a sub-group of electrodes in the X-Y plane in whichsub-area the individual electrodes are represented with a uniquecoordinate.

In another specific embodiment of the invention, the patient controlsthe selection of the electrodes using for example an interactive screenor joystick to move a search field which in this context is a delineatedsubgroup of electrodes in the X-Y plane in which the individualelectrodes are represented with a unique coordinate.

When the search field is moved by use of the joystick or the cursor, oneelectrode is replaced with a new one. In this case it is advantageous ifthe electrodes are grouped in such a way that adjacent electrodes in thetarget tissue also are adjacent in said X-Y plane. In one version, thepatient, while moving around said search field, provides feedback to amicroprocessor or computer by indicating the effectiveness of thepresent selection of electrodes or selection of stimulation parametersof the individual electrodes or groups of electrodes in reducing thesymptoms. This feedback from the patient is stored in the computer. Thisfeedback can be provided verbally by the patient, or for example using acursor on a computer screen. It can also be provided by measuredsignals, such as blood pressure, tremor, EEG or by implanted electrodesin relevant brain centers in the patient or animal. The energy cost foreach selection is also computed and stored together with patientfeedback. Based on several iterations, the computer or microprocessorcalculates the cost benefit ratio for each electrode in order to predictthe optimal selection and stimulation parameters of electrodes.

To optimise the stimulation parameters, the amplitude, frequency etc forthe group may be varied up and down using a joystick or a button whichcan be turned clockwise (signaling increase of the parameter) oranticlockwise (signaling decrease of the parameter) etc, theeffectiveness noted and stored in the computer/database. The parametersmay be further fine tuned by evaluating the effect of each electrodeseparately such that the parameter to be tested is changed selectivelyfor that electrode.

In another embodiment the patient and the physician need not to be inthe same location, since the device associated with the implant and thecomputer controlling the settings of the stimulation may communicateover the internet. E.g. a fine tuning of the stimulation parameters suchas stimulation amplitude, frequency, pulse shape may be made in thisway. This is especially advantageous, since the fine tuning of thestimulation may be performed when the patient is in his home. Also inthis case it is advantageous if the patient first is allowed to getaccustomed with the technique during the surveillance, wherein theconfidence is increased and the anxiety due to the implant is reduced.

Other objectives, features and advantages of the present invention willappear from the detailed disclosure above, from the attached claims, aswell as from the drawings. It is noted that the invention relates to allpossible combinations of features.

Generally, all terms used in the claims are to be interpreted accordingto their ordinary meaning in the technical field, unless explicitlydefined otherwise herein. All references to “a/an/the [electrode,device, step, etc.]” are to be interpreted openly as referring to atleast one instance of said electrode, device, step, etc., unlessexplicitly stated otherwise. The steps of any method disclosed herein donot have to be performed in the exact order disclosed, unless explicitlystated.

As used herein, the term “comprising” and variations of that term arenot intended to exclude other additives, components, integers or steps.

The invention claimed is:
 1. A method for optimization of a stimulationspecificity and an energy consumption of implanted electrodes inexcitable tissue of a patient, the method comprising: electricallystimulating excitable tissue between one or more combinations ofelectrode pairs in a cluster of electrodes, or electrically stimulatingexcitable tissue between one or more combinations of electrode pairs intwo or more clusters of electrodes, wherein the-two electrodes of theelectrode pairs do not belong to a same cluster; wherein each of theelectrodes is located on a physically separated entity, such that thetissue surrounds and separates each electrode from all other electrodes,thereby allowing tissue between the electrodes to be stimulated; whereinthe electrical stimulation between different combinations of electrodepairs in the cluster of electrodes, or the electrical stimulationbetween different combinations of electrode pairs in the two or moreclusters of electrodes, creates a directed electrical field; wherein aneffect of the directed electrical field is assessed after eachelectrical stimulation by registering information provided from thepatient in view of a therapeutic effect and by monitoring an energyconsumption; choosing an electrode pair or pairs which give rise to alowest energy consumption while still giving a therapeutic effect, orassigning each electrode pair a value related to the informationprovided by the patient and the energy consumption, and choosing theelectrode pair or pairs which give(s) rise to a most favorable assignedvalue; and wherein the steps above are preceded by stimulating allelectrodes at a same time while increasing the stimulation strength upto a threshold such that the patient is gradually acquainted to aneffect of stimulation.
 2. The method according to claim 1, whereinpositions of the individual implanted electrodes spread out in thetissue are determined using imaging techniques; and wherein electrodepairs containing electrodes a location of which is previously known togive a therapeutic effect or to not give rise to adverse effects arestimulated.
 3. The method according to claim 1, wherein the electrodesof the electrode pairs are positioned in two different electrodeclusters located close to neurons occupying two separate hemispheres oftissue or in such a way that an electrical field obtained is directedalong a main axis of neurons.
 4. The method according to claim 1,wherein the cluster of electrodes or the two or more clusters ofelectrodes comprises(s) electrodes chosen to be included in astimulation pattern obtained by a method for optimization of thestimulation pattern of a set of implanted electrodes in excitable tissueof a patient, comprising: (a) choosing a first group of a certain numberof electrodes from the set of implanted electrodes, (b) stimulating theexcitable tissue electrically by the first group of electrodes, (c)registering information provided by the patient in response to thestimulation, and (d) assigning each electrode of the first group ofelectrodes a value related to the information, wherein steps (a)-(d) arerepeated for one or more further groups of the certain number ofelectrodes chosen from the set of implanted electrodes, wherein eachelectrode may be included in one or several groups, wherein a totalassigned value for each electrode is calculated, wherein electrodeshaving a total assigned value exceeding a predetermined value or apredetermined number of the electrodes having a highest total assignedvalue are chosen to be included in the stimulation pattern, and whereinsteps (a)-(d) are preceded by stimulating all electrodes at the sametime while increasing the stimulation strength up to a threshold suchthat the patient is gradually acquainted to the effect of stimulation.5. The method according to claim 4, further comprising a secondoptimization of stimulation parameters for the electrodes chosen to beincluded in the stimulation pattern according to claim 4 in view of theenergy consumption needed for the chosen electrodes to give rise to atherapeutic effect, wherein the second optimization comprises: varyingone or more of the stimulation parameters for the chosen electrodes in astimulation test series; registering information provided by thepatient; monitoring the energy consumption for each stimulation testwhere the stimulation gives rise to a therapeutic effect; and choosing,as the stimulation parameters, the parameters which give rise to thelowest energy consumption while still giving a therapeutic effect; orassigning each stimulation test a value related to the informationprovided by the patient and the energy consumption; and choosing theparameters which give rise to the most favorable assigned value.
 6. Themethod according to claim 5, further comprising: optimizing one or morestimulation parameters for the use of the electrodes chosen to beincluded in the stimulation pattern in a stimulation treatment of thepatient, wherein the chosen electrodes are subjected to stimulationtests in which one or more stimulation parameters chosen from the groupcomprising a pulse width, an amplitude of a stimulation pulse, astimulation strength, a stimulation frequency, a temporal pattern ofstimulation, a shape of the stimulation pulse, a polarity, a stimulationtype as to a degree of randomization, amplitude modulation, andfrequency modulation are varied, wherein information provided by thepatient is registered for each stimulation test, wherein each parameterset is assigned a value related to the information, and wherein theparameter set having a most favorable assigned value is chosen to beused for the chosen electrodes during the stimulation treatment, orwherein the one or more stimulation parameters also are used in thestimulation test of the second optimization in view of energyconsumption according to claim
 5. 7. The method according to claim 6,wherein one or more of the amplitude of the stimulation pulse, thestimulation frequency, and the shape of the stimulation pulse are variedin each stimulation test.
 8. The method according to claim 5, furthercomprising: optimizing one or more stimulation parameters for a use ofthe electrodes chosen to be included in the stimulation pattern in astimulation treatment of the patient, wherein the chosen electrodes aresubjected to stimulation tests in which a burst mode is varied, whereininformation provided by the patient is registered for each stimulationtest, wherein each parameter set is assigned a value related to theinformation, and wherein the parameter set having the most favorableassigned value is chosen to be used for the chosen electrodes during thestimulation treatment, or wherein one or more stimulation parametersalso are used in the stimulation test of the second optimization in viewof energy consumption according to claim
 5. 9. The method according toclaim 4, wherein the set of implanted electrodes comprises a pluralityof microelectrodes.
 10. The method according to claim 4, wherein theexcitable tissue is neuronal tissue or endocrine tissue, a heart or avascular system.
 11. The method according to claim 10, wherein theneuronal tissue is brain tissue, spinal cord or peripheral nerves. 12.The method according to claim 11, wherein the brain tissue is selectedfrom the group consisting of subthalamic nucleus (STN), globus pallidusinterna (GPi), periaqueductal grey substance, periventricular grey,internal capsule, ventral posterolateral nucleus, thalamus, striatum,habenula, hypothalamus, basal nucleus of Meynert, cortical areas, brainstem, medial forebrain bundle, internal capsule, amygdala, hippocampus,septum, and ventral posteromedial nucleus.
 13. The method according toclaim 10, wherein the endocrine tissue is selected from the groupcomprising pancreas, pituitary gland and pineal gland.
 14. The methodaccording to claim 4, wherein each group of electrodes is chosenrandomly.
 15. The method according to claim 4, wherein each group ofelectrodes is chosen by: recording of an activity pattern in theexcitable tissue by each implanted electrode, identifying an anatomicalcompartment or type of cells from which the electrode is recording theactivity pattern, comparing the recorded activity pattern withinformation stored in a database, and choosing the group of electrodesto be used for stimulation on a basis of a result of the comparingand/or on a basis of the identified anatomical compartment.
 16. Themethod according to claim 4, wherein each group of electrodes is chosenby: recording of activity pattern in the excitable tissue by eachimplanted electrode, identifying an anatomical compartment or type ofcells from which the electrode is recording the activity pattern, andchoosing the group of electrodes to be used for stimulation on a basisof the recorded activity patterns and/or on a basis of the identifiedanatomical compartment.
 17. The method according to claim 16, furthercomprising: coupling the anatomical compartment or type of cells withthe information from the patient in a database, and couplingcombinations of electrodes which stimulate certain anatomicalcompartments or types of cells to the information from the patient in adatabase.
 18. The method according to claim 4, wherein each group ofelectrodes is chosen by: performing brain scanning, MRI examination, CTexamination and/or ultrasound examination, identifying anatomicalcompartments where the electrodes are located, and choosing the group ofelectrodes on a basis of a location of the electrodes.
 19. The methodaccording to claim 4, wherein a number of electrodes in each group is1-15, or wherein at most 50% of a total number of electrodes areincluded in each group.
 20. The method according to claim 4, wherein theinformation from the patient is a response to an effect of thestimulation perceived by the patient.
 21. The method according to claim4, wherein the information from the patient is a value obtained bymeasuring a physiological, psychological or pathological reaction of thepatient.
 22. The method according to claim 4, wherein the informationfrom the patient is a combination of a response to an effect of thestimulation perceived by the patient and a value obtained by measuring aphysiological, psychological or pathological reaction of the patient.23. The method according to claim 4, wherein the information from thepatient is binary.
 24. The method according to claim 4, wherein theinformation from the patient is given on a scale.
 25. The methodaccording to claim 4, wherein 10-50 different groups of electrodes arestimulated.
 26. The method according to claim 4, wherein the informationfrom the patient is provided by use of a joystick, a touch screen, apad, a computer mouse and/or a trackball.
 27. The method according toclaim 4, wherein the information from the patient is provided via adevice registering eye movements.
 28. The method according to claim 4,wherein the method steps are preceded by a step in which the patient isallowed to get accustomed to a plurality of conditions and equipmentutilized during the stimulation.
 29. The method according to claim 4,wherein the stimulation and the provision of information is performed bythe patient via an electronic connection with a practitioner/physician.30. The method according to claim 4, wherein the method is followed on ascreen device on which the implanted electrodes in the tissue aregraphically represented, and wherein the patient has an ability to scanthe groups of electrodes to stimulate the tissue.
 31. A method fortreatment or alleviation of a disease or condition by use of a set ofelectrodes whose stimulation pattern has been optimized with the methodaccording to claim 4, wherein the disease or condition is chosen fromthe group consisting of brain and/or spinal damage, lost functions,pain, Parkinson's disease, tremor, motor disorders, choreatic and otherinvoluntary movements, memory disorders, Alzheimer's disease,degenerative diseases, epilepsy, mood disorders, aggression, anxiety,phobia, affect, sexual over-activity, impotence, eating disorders, sleepdisorders, such as narcolepsy, attention disorders, stroke, damage ofthe brain, damage of the spinal cord, bladder disorders after spinalcord injury, bowel disorders after spinal cord injury, spasticity,somatosensory disorders, auditory disorders, visual disorders, andolfactory disorders.
 32. A system for optimization of the stimulationpattern of a set of electrodes adapted to be implanted in excitabletissue of a patient and for treatment or alleviation of disease ordisorder with the method according to claim 4, the system comprising: aset of electrodes adapted to be implanted in excitable tissue of apatient, wherein each of the electrodes is located on a physicallyseparated entity, thereby allowing tissue to surround and separate eachelectrode from all other electrodes and allowing tissue between theelectrodes to be stimulated, a stimulation device connected to the setof electrodes and adapted to stimulate the excitable tissue via the setof electrodes, wherein the stimulation device is adapted to activate theset of electrodes at the same time while increasing a stimulationstrength, a first computer program connected to the stimulation deviceand configured to transform information provided by the patient to anassigned value for a tested group of electrodes, to calculate a totalassigned value for each electrode, and to choose a preferred set ofelectrodes to be used for stimulation treatment, wherein the firstcomputer program is configured to choose a group of electrodes from theset of implanted electrodes and to instruct the stimulation device tostimulate the tissue through these electrodes.
 33. The system accordingto claim 32, further comprising: a recording device connected to the setof electrodes and adapted to register an activity pattern in theexcitable tissue, a second computer program connected to the recordingdevice and to the first computer program, and a database connected tothe first computer program and to the second computer program, whereinthe second computer program is configured to compare informationobtained from the recording device in view of the registered activitypattern in the excitable tissue with information in the database in theform of previously registered activity patterns for several patientsregarding the effect of stimulation of the same or similar excitabletissue of the several patients, to choose a collection of usefulelectrodes with the basis on the comparison of activity patterns, and totransform the information about the chosen electrodes to the firstcomputer program, wherein said first computer program is configured totransmit the information provided by the patient to the database forstorage.
 34. The system according to claim 32, wherein the set ofimplanted electrodes comprises a plurality of microelectrodes.
 35. Thesystem according to claim 32, further comprising a joystick, a touchscreen, a tablet, a computer mouse and/or a trackball, wherein thejoystick, touch screen, pad, computer mouse and/or trackball is used bythe patient to provide the first computer program with information. 36.The system according to claim 32, further comprising a deviceregistering eye movements, wherein the device registering eye movementsis used by the patient to provide the first computer program withinformation.
 37. The system according to claim 32, further comprising ascreen device on which the implanted electrodes in the tissue aregraphically represented.